Circadian rhythm in pro-arrhythmic activity of pulmonary vein cardiomyocytes

• DOI: 10.1093/europace/euae102.615
• Publication Date: 2024-05-24T12:30:49Z
• Authors: L M K Pannell; A Carpenter; F Segers; Y Z Koh; S C Harmer; H D Piggins; J C Hancox; A F James
• Keywords: 03 medical and health sciences; 0302 clinical medicine; Basic science

Abstract Introduction Cardiomyocytes in the pulmonary vein (PV) sleeves are a major source of ectopic activity driving atrial fibrillation (AF) and episodes AF patients more prevalent at night. While it is known that circadian clocks within heart regionally control 24-hour variation pacemaking ventricular repolarisation, mechanisms underlying nighttime preponderance unknown. Purpose This study addresses hypothesis rhythms exist pro-arrhythmic PV cardiomyocytes. Methods Male Wistar rats maintained cycle 12-hr light/dark (lights-on Zeitgeber time, ZT=0; lights-off, ZT12) were subject to terminal general anaesthesia (140 mg/kg Na pentobarbital i.p.) ZT=0, 6, 12 or 18 hr hearts removed. RNA was extracted from left (LA) appendage (LAA) proximal LA/PV junction (3 per ZT) sequencing conducted. Reads mapped rat genome, counts normalised models which ZT not included as factor compared (Likelihood Ratio Test, adjusted-P<0.01). Whole-cell current clamp recordings made cardiomyocytes isolated (n=308) LAA (n=264) (N=74 rats). The effects noradrenaline (NA, 1 µM) acetylcholine (ACh, examined. Data plotted against time recording fitted sine wave establish rhythmicity (P<0.05, extra-sum-of-squares F-test). effect ≥24 constant dark period immediately before experiment reported mean ± standard error. Results expression 1368 genes varied significantly with ZT, including clock components (e.g. Bmal1, Per1). cells larger than (73±1.6 pF vs 53±1.3 pF, P<0.0001) had depolarised resting membrane potential (-69±0.2 mV -72±0.1 mV, P<0.0001). Both cell types showed action duration 90% repolarisation (APD90) frequency activity. Pro-arrhythmic greatest greater during rest phase (ZT0-12) both types. In contrast, rhythm APD90 differed between type, longest APD­­90 recorded active (ZT12-24) but cells. increased by NA decreased ACh maximal phase. Conclusion Circadian proarrhythmic-activity has been demonstrated cardiomyocytes, differences two suggests presence peripheral Understanding these important development future therapeutic options for AF.